Project Summary/Abstract Although HIV-infected patients in the western world have a life expectancy near that of the general population, they are at a significantly elevated risk of developing HIV-associated neurocognitive disorders (HAND). Such disorders are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected patients, and research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). While the mechanisms that underlie HAND are not well understood, numerous human neuroimaging studies have examined the brain regions that may be involved, and overall these studies have been largely successful in identifying the critical hubs and large-scale networks. However, many questions remain regarding basic circuit dysfunction within these brain regions, and consequently there is a clear and common need to further investigate the key physiological parameters that may underlie the development and progression of HAND, especially in the context of aging. It is well known that human cortical neurons exhibit spontaneous firing in the absence of incoming exogenous and endogenous input. Across a neuronal population, these discharges summate with local dendritic currents and synaptic potentials to produce cortical rhythmic activity, which is often referred to as ?spontaneous activity.? Such spontaneous rhythms are ubiquitous throughout the human brain, but their role in modulating cognition is only beginning to be understood. Recently, we used magnetoencephalography (MEG) to show that the strength of spontaneous activity directly affects neural oscillatory activity in the same cortical area, and in-turn modulates real time task performance in controls and HIV-infected adults. Additionally, we have shown that spontaneous activity in multiple brain regions increases with advancing age, that this increase is deleterious to performance, and that these effects are accentuated in patients with HAND. In fact, our preliminary data suggests that the level of spontaneous activity in specific brain regions may distinguish age-matched HIV-infected patients with and without HAND. In this project, we will quantify the trajectory of age-related elevations in spontaneous cortical activity in a large group of HIV-infected adults and demographically-matched controls. We will then evaluate how the strength of such spontaneous activity affects local neural oscillations and real time cognitive performance. Based on extensive preliminary data, we hypothesize that spontaneous activity will increase with age in both groups, and that the slope of this increase will be steeper in HIV-infected adults relative to controls, and further accentuated in those with HAND. Importantly, we also hypothesize that these increases will be associated with proportional changes in the strength of the neural oscillations underlying cognition, and behavioral performance indices such as accuracy and reaction time. Finally, in Aim 3, we will utilize deep learning methods to classify our sample into groups based on the neurophysiological metrics derived from MEG, with the gold standard being their overall neuropsychological profile.